Effects of somatostatin receptor type 2 antagonism during insulin-induced hypoglycaemia in male rats with prediabetes

Aims

To examine if glucagon counterregulatory defects exist in a rat model of prediabetes (pre-T2D) and to assess if a selective somatostatin receptor 2 antagonist (SSTR2a), ZT-01, enhances the glucagon response to insulin-induced hypoglycaemia.

Materials and methods

Hyperglycaemia was induced in 8- to 9-week-old male, Sprague-Dawley rats via 7 weeks of high-fat diet followed by a single, low-dose intraperitoneal injection of streptozotocin (30 mg/kg). After 2 weeks of basal insulin therapy (0-4 U/d insulin glargine, administered subcutaneously [SC]) to facilitate partial glycaemic recovery and a pre-T2D phenotype, n = 17 pre-T2D and n = 10 normal chow-fed control rats underwent the first of two hypoglycaemic treatment-crossover experiments, separated by a 1-week washout period. On each experimental day, SSTR2a (3 mg/kg ZT-01, SC) or vehicle was administered 1 hour prior to insulin-induced hypoglycaemia (insulin aspart, 6 U/kg, SC).

Results

Glucagon counterregulation was marginally reduced with the induction of pre-T2D. Treatment with SSTR2a raised peak plasma glucagon levels and glucagon area under the curve before and after insulin overdose in both and pre-T2D rats. Blood glucose concentration was elevated by 30 minutes after SSTR2a treatment in pre-T2D rats, and hypoglycaemia onset (≤3.9 mmol/L) was delayed by 15 ± 12 minutes compared with vehicle (P < 0.001), despite similar glucose nadirs in the two treatment groups (1.4 ± 0.3 mmol/L). SSTR2a treatment had no effect on blood glucose levels in the control group or on the hypoglycaemia-induced decline in plasma C-peptide levels in either group.

Conclusions

Treatment with an SSTR2a increases glucagon responsiveness and delays the onset of insulin-induced hypoglycaemia in this rat model of pre-T2D where only a modest deficiency in glucagon counterregulation exists.